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Research of epigenetic aspects of hematopoietic and spermatogenesis stem cells.
Hybešová, Michaela ; Pimková, Kristýna (advisor) ; Děd, Lukáš (referee)
Stem cell differentiation is controlled by coordinated regulation of gene transcription. One of the regulatory factors is the loosening of chromatin and the accessibility of DNA to transcription factors. Chromatin remodeling is mediated by remodeling complexes. The ISWI chromatin remodeling ATPase Smarca5 (S5) is an important factor of remodeling complexes. It is a highly conserved chromatin-remodeling factor forming a catalytic subunit that can be found in several oligosubunit complexes. In these complexes, it actively regulates nucleosome structure and remodeling during DNA replication, repair and transcription. S5 has been identified as a key protein in embryonic development. Its deficiency leads to defects in hematopoiesis and male genital development. In the presented study, we focused on the role of S5 in hematopoiesis and spermatogenesis. Using a mouse model with transgenic expression of S5, co-immunoprecipitation and mass spectrometry, we identified S5 complexes in hematopoietic and testicular cells. We also studied the phenotypic consequences of S5 deficiency in mouse testes and found that it leads to impaired sperm development and male sterility. Using transcriptomic and proteomic analysis, we identified several molecular programs that could lead to reproductive disorders. Our work...
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Leukemic stem cells
Vobořil, Matouš ; Stöckbauer, Petr (advisor) ; Šídová, Monika (referee)
The biology of stem cells came to the foreground not only due to scientific but also due to clinical interest and it is one of the most developing fields of current biomedical research. The idea, that all tumor cells contain population of cells like stem cells, leads to the "cancer stem cells hypothesis". It says, that each tumor cell contains small population of cells capable to initiate and maintain the tumor growth. Tumors of the hematopoietic tissue were the first, where cancer or leukemic stem cells were isolated. Therefore, leukemic stem cells are so far the best understood cancer stem cells. However, despite the huge advances in the biology of leukemic stem cells, there are many properties still unknown. This thesis initially presents basic knowledges in the stem cell biology, including their origin and identification. Later it focuses on the stem cell hypothesis and describes of the main properties of stem cells in solid tumors. The main part of this thesis also shows in details the origin and properties of the leukemic stem cells and decribes some new directions in the targeted therapy of hematological malignancies.
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Leukemic stem cells
Vobořil, Matouš ; Stöckbauer, Petr (advisor) ; Šídová, Monika (referee)
The biology of stem cells came to the foreground not only due to scientific but also due to clinical interest and it is one of the most developing fields of current biomedical research. The idea, that all tumor cells contain population of cells like stem cells, leads to the "cancer stem cells hypothesis". It says, that each tumor cell contains small population of cells capable to initiate and maintain the tumor growth. Tumors of the hematopoietic tissue were the first, where cancer or leukemic stem cells were isolated. Therefore, leukemic stem cells are so far the best understood cancer stem cells. However, despite the huge advances in the biology of leukemic stem cells, there are many properties still unknown. This thesis initially presents basic knowledges in the stem cell biology, including their origin and identification. Later it focuses on the stem cell hypothesis and describes of the main properties of stem cells in solid tumors. The main part of this thesis also shows in details the origin and properties of the leukemic stem cells and decribes some new directions in the targeted therapy of hematological malignancies.
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Origins of vertebrate hematiopoiesis
Svoboda, Ondřej ; Bartůněk, Petr (advisor) ; Divoký, Vladimír (referee) ; Živný, Jan (referee)
(ENGLISH) Hematopoiesis is dependent on the actions of hematopoietic stem cells (HSCs). This process is tightly controlled through a complex array of extrinsic and intrinsic factors. Even though the hematopoiesis seems to be well conserved across the disparate vertebrate animals, erythroid and thrombocytic differentiation have changed during the evolution of mammals. Specifically, adult mammalian red blood cells have the unique feature of being enucleated, and mammalian thrombocytes are not individual cells, but fragments of megakaryocytes, instead. It is likely that these enhancements provided a survival advantage to early mammalian species; however, they also bring up the question of evolutionary origin of these cells that studied using zebrafish (Danio rerio) model. First, it was necessary to generate a toolbox of a recombinant cytokines and optimized culture media that allowed us to manipulate zebrafish hematopoietic cells ex vivo in liquid and clonal cultures. Interestingly, teleost species underwent an extra duplication event during their evolution and as a result, two copies (paralogs) of some of the genes are present in zebrafish. This was also the case for majority of the cytokines from our toolbox and here, we provide functional characterization of these paralogs. Strikingly, our results...
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